Skip to main content
SpringerLink
Log in

Opioid Receptor Dimerization

  • Chapter
  • First Online:
The Opiate Receptors

Part of the book series: The Receptors ((REC))

Abstract

Opioid receptors are the primary clinical targets for the attenuation of pain. Many opiates used for pain management have a high abuse liability due to their psychoactive and rewarding properties. In recent years, accumulating evidence obtained through an array of techniques (from biochemical to pharmacological and biophysical) demonstrate that these receptors exist as homomers/oligomers, and more importantly, that they also form heteromers with closely or distantly related GPCRs. Heteromerization of opioid receptors has profound effects on their maturation, pharmacology, signaling, and trafficking. In addition, heteromer levels are regulated by pathophysiological conditions and by chronic drug treatment, underscoring their importance in the regulation of receptor properties. In this chapter, we describe evidence for opioid receptor homo- and heteromerization, we document the types of opioid receptor-containing heteromers and summarize their most important features, and finally, we discuss the relevance of developing selective ligands targeting heteromers. The interaction of such molecules with a specialized pool of receptors, within a given heteromer, could enhance greater therapeutic activity without undesired effects. This is particularly relevant for the treatment of pain and other related disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bulenger S, Marullo S, Bouvier M (2005) Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation. Trends Pharmacol Sci 26(3):131–137

    PubMed  CAS  Google Scholar 

  2. Rozenfeld R, Abul-Husn NS, Gomez I, Devi LA (2007) An emerging role for the delta opioid receptor in the regulation of mu opioid receptor function. Sci World J 7:64–73

    Google Scholar 

  3. Limbird LE, Meyts PD, Lefkowitz RJ (1975) Beta-adrenergic receptors: evidence for negative cooperativity. Biochem Biophys Res Commun 64(4):1160–1168

    PubMed  CAS  Google Scholar 

  4. Limbird LE, Lefkowitz RJ (1976) Negative cooperativity among beta-adrenergic receptors in frog erythrocyte membranes. J Biol Chem 251(16):5007–5014

    PubMed  CAS  Google Scholar 

  5. Mattera R, Pitts BJ, Entman ML, Birnbaumer L (1985) Guanine nucleotide regulation of a mammalian myocardial muscarinic receptor system. Evidence for homo- and heterotropic cooperativity in ligand binding analyzed by computer-assisted curve fitting. J Biol Chem 260(12):7410–7421

    PubMed  CAS  Google Scholar 

  6. Potter LT, Ballesteros LA, Bichajian LH et al (1991) Evidence of paired M2 muscarinic receptors. Mol Pharmacol 39(2):211–221

    PubMed  CAS  Google Scholar 

  7. Hirschberg BT, Schimerlik MI (1994) A kinetic model for oxotremorine M binding to recombinant porcine m2 muscarinic receptors expressed in Chinese hamster ovary cells. J Biol Chem 269(42):26127–26135

    PubMed  CAS  Google Scholar 

  8. Wreggett KA, Wells JW (1995) Cooperativity manifest in the binding properties of purified cardiac muscarinic receptors. J Biol Chem 270(38):22488–22499

    PubMed  CAS  Google Scholar 

  9. Agnati LF, Fuxe K, Zoli M, Rondanini C, Ogren SO (1982) New vistas on synaptic plasticity: the receptor mosaic hypothesis of the engram. Med Biol 60(4):183–190

    PubMed  CAS  Google Scholar 

  10. Conn PM, Rogers DC, Stewart JM, Niedel J, Sheffield T (1982) Conversion of a gonadotropin-releasing hormone antagonist to an agonist. Nature 296(5858):653–655

    PubMed  CAS  Google Scholar 

  11. Fraser CM, Venter JC (1982) The size of the mammalian lung beta 2-adrenergic receptor as determined by target size analysis and immunoaffinity chromatography. Biochem Biophys Res Commun 109(1):21–29

    PubMed  CAS  Google Scholar 

  12. Venter JC (1983) Muscarinic cholinergic receptor structure. Receptor size, membrane orientation, and absence of major phylogenetic structural diversity. J Biol Chem 258(8):4842–4848

    PubMed  CAS  Google Scholar 

  13. Venter JC, Horne P, Eddy B, Greguski R, Fraser CM (1984) Alpha 1-adrenergic receptor structure. Mol Pharmacol 26(2):196–205

    PubMed  CAS  Google Scholar 

  14. Lilly L, Fraser CM, Jung CY, Seeman P, Venter JC (1983) Molecular size of the canine and human brain D2 dopamine receptor as determined by radiation inactivation. Mol Pharmacol 24(1):10–14

    PubMed  CAS  Google Scholar 

  15. Conn PM, Venter JC (1985) Radiation inactivation (target size analysis) of the gonadotropin-releasing hormone receptor: evidence for a high molecular weight complex. Endocrinology 116(4):1324–1326

    PubMed  CAS  Google Scholar 

  16. Frame LT, Yeung SM, Venter JC, Cooper DM (1986) Target size of the adenosine Ri receptor. Biochem J 235(2):621–624

    PubMed  CAS  Google Scholar 

  17. Herberg JT, Codina J, Rich KA, Rojas FJ, Iyengar R (1984) The hepatic glucagon receptor. Solubilization, characterization, and development of an affinity adsorption assay for the soluble receptor. J Biol Chem 259(14):9285–9294

    PubMed  CAS  Google Scholar 

  18. Maggio R, Vogel Z, Wess J (1993) Coexpression studies with mutant muscarinic/adrenergic receptors provide evidence for intermolecular “cross-talk” between G-protein-linked receptors. Proc Natl Acad Sci USA 90(7):3103–3107

    PubMed  CAS  Google Scholar 

  19. Monnot C, Bihoreau C, Conchon S, Curnow KM, Corvol P, Clauser E (1996) Polar residues in the transmembrane domains of the type 1 angiotensin II receptor are required for binding and coupling. Reconstitution of the binding site by co-expression of two deficient mutants. J Biol Chem 271(3):1507–1513

    PubMed  CAS  Google Scholar 

  20. Fotiadis D, Liang Y, Filipek S, Saperstein DA, Engel A, Palczewski K (2003) Atomic-force microscopy: Rhodopsin dimers in native disc membranes. Nature 421(6919):127–128

    PubMed  CAS  Google Scholar 

  21. Liang Y, Fotiadis D, Filipek S, Saperstein DA, Palczewski K, Engel A (2003) Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes. J Biol Chem 278(24):21655–21662

    PubMed  CAS  Google Scholar 

  22. Davies A, Gowen BE, Krebs AM, Schertler GF, Saibil HR (2001) Three-dimensional structure of an invertebrate rhodopsin and basis for ordered alignment in the photoreceptor membrane. J Mol Biol 314(3):455–463

    PubMed  CAS  Google Scholar 

  23. Rasmussen SG, Choi HJ, Rosenbaum DM et al (2007) Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 450(7168):383–387

    PubMed  CAS  Google Scholar 

  24. Rosenbaum DM, Cherezov V, Hanson MA et al (2007) GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science 318(5854):1266–1273

    PubMed  CAS  Google Scholar 

  25. Jones KA, Borowsky B, Tamm JA et al (1998) GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature 396(6712):674–679

    PubMed  CAS  Google Scholar 

  26. White JH, Wise A, Main MJ et al (1998) Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature 396(6712):679–682

    PubMed  CAS  Google Scholar 

  27. Kaupmann K, Malitschek B, Schuler V et al (1998) GABA(B)-receptor subtypes assemble into functional heteromeric complexes. Nature 396(6712):683–687

    PubMed  CAS  Google Scholar 

  28. Kuner R, Kohr G, Grunewald S, Eisenhardt G, Bach A, Kornau HC (1999) Role of heteromer formation in GABAB receptor function. Science 283(5398):74–77

    PubMed  CAS  Google Scholar 

  29. Nelson G, Chandrashekar J, Hoon MA et al (2002) An amino-acid taste receptor. Nature 416(6877):199–202

    PubMed  CAS  Google Scholar 

  30. Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ, Zuker CS (2001) Mammalian sweet taste receptors. Cell 106(3):381–390

    PubMed  CAS  Google Scholar 

  31. Cui M, Jiang P, Maillet E, Max M, Margolskee RF, Osman R (2006) The heterodimeric sweet taste receptor has multiple potential ligand binding sites. Curr Pharm Des 12(35):4591–4600

    PubMed  CAS  Google Scholar 

  32. Cvejic S, Devi LA (1997) Dimerization of the delta opioid receptor: implication for a role in receptor internalization. J Biol Chem 272(43):26959–26964

    PubMed  CAS  Google Scholar 

  33. Jordan BA, Devi LA (1999) G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399(6737):697–700

    PubMed  CAS  Google Scholar 

  34. He L, Fong J, von Zastrow M, Whistler JL (2002) Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization. Cell 108(2):271–282

    PubMed  CAS  Google Scholar 

  35. Gomes I, Jordan BA, Gupta A, Rios C, Trapaidze N, Devi LA (2001) G protein-coupled receptor dimerization: implications in modulating receptor function. J Mol Med 79(5–6):226–242

    PubMed  CAS  Google Scholar 

  36. Rios CD, Jordan BA, Gomes I, Devi LA (2001) G-protein-coupled receptor dimerization: modulation of receptor function. Pharmacol Ther 92(2–3):71–87

    PubMed  CAS  Google Scholar 

  37. Gomes I, Filipovska J, Jordan BA, Devi LA (2002) Oligomerization of opioid receptors. Methods 27(4):358–365

    PubMed  CAS  Google Scholar 

  38. Ramsay D, Kellett E, McVey M, Rees S, Milligan G (2002) Homo- and hetero-oligomeric interactions between G-protein-coupled receptors in living cells monitored by two variants of bioluminescence resonance energy transfer (BRET): hetero-oligomers between receptor subtypes form more efficiently than between less closely related sequences. Biochem J 365(pt 2):429–440

    PubMed  CAS  Google Scholar 

  39. Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, Devi LA (2004) A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc Natl Acad Sci USA 101(14):5135–5139

    PubMed  CAS  Google Scholar 

  40. Wang D, Sun X, Bohn LM, Sadee W (2005) Opioid receptor homo- and heterodimerization in living cells by quantitative bioluminescence resonance energy transfer. Mol Pharmacol 67(6):2173–2184

    PubMed  CAS  Google Scholar 

  41. Filizola M, Laakkonen L, Loew GH (1999) 3D modeling, ligand binding and activation studies of the cloned mouse delta, mu; and kappa opioid receptors. Protein Eng 12(11):927–942

    PubMed  CAS  Google Scholar 

  42. Filizola M, Villar HO, Loew GH (2001) Molecular determinants of nonspecific recognition of delta, mu, and kappa opioid receptors. Bioorg Med Chem 9(1):69–76

    PubMed  CAS  Google Scholar 

  43. Filizola M, Olmea O, Weinstein H (2002) Prediction of heterodimerization interfaces of G-protein-coupled receptors with a new subtractive correlated mutation method. Protein Eng 15(11):881–885

    PubMed  CAS  Google Scholar 

  44. Filizola M, Weinstein H (2002) Structural models for dimerization of G-protein-coupled receptors: the opioid receptor homodimers. Biopolymers 66(5):317–325

    PubMed  CAS  Google Scholar 

  45. He L, Whistler JL (2007) The biochemical analysis of methadone modulation on morphine-induced tolerance and dependence in the rat brain. Pharmacology 79(4):193–202

    PubMed  CAS  Google Scholar 

  46. Jiang Q, Takemori AE, Sultana M et al (1991) Differential antagonism of opioid delta antinociception by [D-Ala2, Leu5, Cys6]enkephalin and naltrindole 5′-isothiocyanate: evidence for delta receptor subtypes. J Pharmacol Exp Ther 257(3):1069–1075

    PubMed  CAS  Google Scholar 

  47. Zukin RS, Eghbali M, Olive D, Unterwald EM, Tempel A (1988) Characterization and visualization of rat and guinea pig brain kappa opioid receptors: evidence for kappa 1 and kappa 2 opioid receptors. Proc Natl Acad Sci USA 85(11):4061–4065

    PubMed  CAS  Google Scholar 

  48. Bhushan RG, Sharma SK, Xie Z, Daniels DJ, Portoghese PS (2004) A bivalent ligand (KDN-21) reveals spinal delta and kappa opioid receptors are organized as heterodimers that give rise to delta(1) and kappa(2) phenotypes. Selective targeting of delta-kappa heterodimers. J Med Chem 47(12):2969–2972

    PubMed  CAS  Google Scholar 

  49. Townsend DT, Portoghese PS, Brown DR (2004) Characterization of specific opioid binding sites in neural membranes from the myenteric plexus of porcine small intestine. J Pharmacol Exp Ther 308(1):385–93

    PubMed  Google Scholar 

  50. Xie Z, Bhushan RG, Daniels DJ, Portoghese PS (2005) Interaction of bivalent ligand KDN21 with heterodimeric delta-kappa opioid receptors in human embryonic kidney 293 cells. Mol Pharmacol 68(4):1079–1086

    PubMed  CAS  Google Scholar 

  51. Vaught JL, Takemori AE (1979) A further characterization of the differential effects of leucine enkephalin, methionine enkephalin and their analogs on morphine-induced analgesia. J Pharmacol Exp Ther 211(2):280–283

    PubMed  CAS  Google Scholar 

  52. Vaught JL, Takemori AE (1979) Differential effects of leucine and methionine enkephalin on morphine-induced analgesia, acute tolerance and dependence. J Pharmacol Exp Ther 208(1):86–90

    PubMed  CAS  Google Scholar 

  53. Rothman RB, Bowen WD, Herkenham M, Jacobson AE, Rice KC, Pert CB (1985) A quantitative study of [3H]D-Ala2-D-Leu5-enkephalin binding to rat brain membranes. Evidence that oxymorphone is a noncompetitive inhibitor of the lower affinity delta-binding site. Mol Pharmacol 27(3):399–409

    PubMed  CAS  Google Scholar 

  54. Rothman RB, Long JB, Bykov V, Jacobson AE, Rice KC, Holaday JW (1988) beta-FNA binds irreversibly to the opiate receptor complex: in vivo and in vitro evidence. J Pharmacol Exp Ther 247(2):405–416

    PubMed  CAS  Google Scholar 

  55. Rutherford JM, Wang J, Xu H et al (2008) Evidence for a mu-delta opioid receptor complex in CHO cells co-expressing mu and delta opioid peptide receptors. Peptides 29(8):1424–1431

    PubMed  CAS  Google Scholar 

  56. Bowen WD, Gentleman S, Herkenham M, Pert CB (1981) Interconverting mu and delta forms of the opiate receptor in rat striatal patches. Proc Natl Acad Sci USA 78(8):4818–4822

    PubMed  CAS  Google Scholar 

  57. D’Amato R, Holaday JW (1984) Multiple opioid receptors in endotoxic shock: evidence for delta involvement and mu-delta interactions in vivo. Proc Natl Acad Sci USA 81(9):2898–2901

    PubMed  Google Scholar 

  58. Tortella FC, Robles L, Holaday JW (1985) The anticonvulsant effects of DADLE are primarily mediated by activation of delta opioid receptors: interactions between delta and mu receptor antagonists. Life Sci 37(6):497–503

    PubMed  CAS  Google Scholar 

  59. Holaday JW, Tortella FC, Maneckjee R, Long JB (1986) In vivo interactions among opiate receptor agonists and antagonists. NIDA Res Monogr 71:173–188

    PubMed  CAS  Google Scholar 

  60. Schoffelmeer AN, Yao YH, Simon EJ (1990) Cross-linking of 125I-beta-endorphin to rat striatal mu- and delta-opioid receptors under physiological conditions: evidence for an opioid receptor complex. Prog Clin Biol Res 328:105–108

    PubMed  CAS  Google Scholar 

  61. Garzon J, Juarros JL, Castro MA, Sanchez-Blazquez P (1995) Antibodies to the cloned mu-opioid receptor detect various molecular weight forms in areas of mouse brain. Mol Pharmacol 47(4):738–744

    PubMed  CAS  Google Scholar 

  62. Traynor JR, Elliott J (1993) Delta-opioid receptor subtypes and cross-talk with mu-receptors. Trends Pharmacol Sci 14(3):84–86

    PubMed  CAS  Google Scholar 

  63. Porreca F, Takemori AE, Sultana M, Portoghese PS, Bowen WD, Mosberg HI (1992) Modulation of mu-mediated antinociception in the mouse involves opioid delta-2 receptors. J Pharmacol Exp Ther 263(1):147–152

    PubMed  CAS  Google Scholar 

  64. Abdelhamid EE, Takemori AE (1991) Characteristics of mu and delta opioid binding sites in striatal slices of morphine-tolerant and -dependent mice. Eur J Pharmacol 198(2–3):157–163

    PubMed  CAS  Google Scholar 

  65. Zhu Y, King MA, Schuller AG et al (1999) Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron 24(1):243–252

    PubMed  CAS  Google Scholar 

  66. Abul-Husn NS, Sutak M, Milne B, Jhamandas K (2007) Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of mu- and delta-opioid receptor antagonists. Br J Pharmacol 151(6):877–887

    PubMed  CAS  Google Scholar 

  67. Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA (2000) Heterodimerization of mu and delta opioid receptors: a role in opiate synergy. J Neurosci 20(22):RC110

    PubMed  CAS  Google Scholar 

  68. George SR, Fan T, Xie Z et al (2000) Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties. J Biol Chem 275(34):26128–26135

    PubMed  CAS  Google Scholar 

  69. Snook LA, Milligan G, Kieffer BL, Massotte D (2006) Mu-delta opioid receptor functional interaction: insight using receptor-G protein fusions. J Pharmacol Exp Ther 318(2):683–690

    PubMed  CAS  Google Scholar 

  70. Fan T, Varghese G, Nguyen T, Tse R, O’Dowd BF, George SR (2005) A role for the distal carboxyl tails in generating the novel pharmacology and G protein activation profile of mu and delta opioid receptor hetero-oligomers. J Biol Chem 280(46):38478–38488

    PubMed  CAS  Google Scholar 

  71. Rozenfeld R, Devi LA (2007) Receptor heterodimerization leads to a switch in signaling: beta-arrestin2-mediated ERK activation by mu-delta opioid receptor heterodimers. FASEB J 21(10):2455–2465

    PubMed  CAS  Google Scholar 

  72. Walwyn W, John S, Maga M, Evans CJ, Hales TG (2009) Delta receptors are required for full inhibitory coupling of mu-receptors to voltage-dependent Ca2+ channels in dorsal root ganglion neurons. Mol Pharmacol 76(1):134–143

    PubMed  CAS  Google Scholar 

  73. Charles AC, Mostovskaya N, Asas K, Evans CJ, Dankovich ML, Hales TG (2003) Coexpression of delta-opioid receptors with micro receptors in GH3 cells changes the functional response to micro agonists from inhibitory to excitatory. Mol Pharmacol 63(1):89–95

    PubMed  CAS  Google Scholar 

  74. Hasbi A, Nguyen T, Fan T et al (2007) Trafficking of preassembled opioid mu-delta heterooligomer-Gz signaling complexes to the plasma membrane: coregulation by agonists. Biochemistry 46(45):12997–13009

    PubMed  CAS  Google Scholar 

  75. Law PY, Erickson-Herbrandson LJ, Zha QQ et al (2005) Heterodimerization of mu- and delta-opioid receptors occurs at the cell surface only and requires receptor-G protein interactions. J Biol Chem 280(12):11152–11164

    PubMed  CAS  Google Scholar 

  76. Decaillot FM, Rozenfeld R, Gupta A, Devi LA (2008) Cell surface targeting of mu-delta opioid receptor heterodimers by RTP4. Proc Natl Acad Sci USA 105(41):16045–16050

    PubMed  CAS  Google Scholar 

  77. Drasner K, Fields HL (1988) Synergy between the antinociceptive effects of intrathecal clonidine and systemic morphine in the rat. Pain 32(3):309–312

    PubMed  CAS  Google Scholar 

  78. Ossipov MH, Lopez Y, Bian D, Nichols ML, Porreca F (1997) Synergistic antinociceptive interactions of morphine and clonidine in rats with nerve-ligation injury. Anesthesiology 86(1):196–204

    PubMed  CAS  Google Scholar 

  79. Stone LS, MacMillan LB, Kitto KF, Limbird LE, Wilcox GLP (1997) The alpha2a adrenergic receptor subtype mediates spinal analgesia evoked by alpha2 agonists and is necessary for spinal adrenergic-opioid synergy. J Neurosci 17(18):7157–7165

    PubMed  CAS  Google Scholar 

  80. Jordan BA, Gomes I, Rios C, Filipovska J, Devi LA (2003) Functional interactions between mu opioid and alpha 2A-adrenergic receptors. Mol Pharmacol 64(6):1317–1324

    PubMed  CAS  Google Scholar 

  81. Vilardaga JP, Nikolaev VO, Lorenz K, Ferrandon S, Zhuang Z, Lohse MJ (2008) Conformational cross-talk between alpha2A-adrenergic and mu-opioid receptors controls cell signaling. Nat Chem Biol 4(2):126–131

    PubMed  CAS  Google Scholar 

  82. Zhang YQ, Limbird LE (2004) Hetero-oligomers of alpha2A-adrenergic and mu-opioid receptors do not lead to transactivation of G-proteins or altered endocytosis profiles. Biochem Soc Trans 32(Pt 5):856–860

    PubMed  CAS  Google Scholar 

  83. Manzanares J, Corchero J, Fuentes JA (1999) Opioid and cannabinoid receptor-mediated regulation of the increase in adrenocorticotropin hormone and corticosterone plasma concentrations induced by central administration of delta(9)-tetrahydrocannabinol in rats. Brain Res 839(1):173–179

    PubMed  CAS  Google Scholar 

  84. Cichewicz DL, Cox ML, Welch SP, Selley DE, Sim-Selley LJ (2004) Mu and delta opioid-stimulated [35S]GTP gamma S binding in brain and spinal cord of polyarthritic rats. Eur J Pharmacol 504(1–2):33–38

    PubMed  CAS  Google Scholar 

  85. Ledent C, Valverde O, Cossu G et al (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283(5400):401–404

    PubMed  CAS  Google Scholar 

  86. Ghozland S, Matthes HW, Simonin F, Filliol D, Kieffer BL, Maldonado R (2002) Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors. J Neurosci 22(3):1146–1154

    PubMed  CAS  Google Scholar 

  87. Rodriguez JJ, Mackie K, Pickel VM (2001) Ultrastructural localization of the CB1 cannabinoid receptor in mu-opioid receptor patches of the rat Caudate putamen nucleus. J Neurosci 21(3):823–833

    PubMed  CAS  Google Scholar 

  88. Salio C, Fischer J, Franzoni MF, Mackie K, Kaneko T, Conrath M (2001) CB1-cannabinoid and mu-opioid receptor co-localization on postsynaptic target in the rat dorsal horn. Neuroreport 12(17):3689–3692

    PubMed  CAS  Google Scholar 

  89. Pickel VM, Chan J, Kash TL, Rodriguez JJ, MacKie K (2004) Compartment-specific localization of cannabinoid 1 (CB1) and mu-opioid receptors in rat nucleus accumbens. Neuroscience 127(1):101–112

    PubMed  CAS  Google Scholar 

  90. Rios C, Gomes I, Devi LA (2006) mu opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis. Br J Pharmacol 148(4):387–395

    PubMed  CAS  Google Scholar 

  91. Hojo M, Sudo Y, Ando Y et al (2008) mu-Opioid receptor forms a functional heterodimer with cannabinoid CB1 receptor: electrophysiological and FRET assay analysis. J Pharmacol Sci 108(3):308–319

    PubMed  CAS  Google Scholar 

  92. Becker A, Grecksch G, Kraus J et al (2001) Loss of locomotor sensitisation in response to morphine in D1 receptor deficient mice. Naunyn Schmiedebergs Arch Pharmacol 363(5):562–568

    PubMed  CAS  Google Scholar 

  93. Juhasz JR, Hasbi A, Rashid AJ, So CH, George SR, O’Dowd BF (2008) Mu-opioid receptor heterooligomer formation with the dopamine D1 receptor as directly visualized in living cells. Eur J Pharmacol 581(3):235–243

    PubMed  CAS  Google Scholar 

  94. Calo G, Guerrini R, Rizzi A, Salvadori S, Regoli D (2000) Pharmacology of nociceptin and its receptor: a novel therapeutic target. Br J Pharmacol 129(7):1261–1283

    PubMed  CAS  Google Scholar 

  95. Mogil JS, Pasternak GW (2001) The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol Rev 53(3):381–415

    PubMed  CAS  Google Scholar 

  96. Grisel JE, Mogil JS, Belknap JK, Grandy DK (1996) Orphanin FQ acts as a supraspinal, but not a spinal, anti-opioid peptide. Neuroreport 7(13):2125–2129

    PubMed  CAS  Google Scholar 

  97. Mogil JS, Grisel JE, Reinscheid RK, Civelli O, Belknap JK, Grandy DK (1996) Orphanin FQ is a functional anti-opioid peptide. Neuroscience 75(2):333–337

    PubMed  CAS  Google Scholar 

  98. Calo G, Rizzi A, Marzola G et al (1998) Pharmacological characterization of the nociceptin receptor mediating hyperalgesia in the mouse tail withdrawal assay. Br J Pharmacol 125(2):373–378

    PubMed  CAS  Google Scholar 

  99. Wang HL, Hsu CY, Huang PC et al (2005) Heterodimerization of opioid receptor-like 1 and mu-opioid receptors impairs the potency of micro receptor agonist. J Neurochem 92(6):1285–1294

    PubMed  CAS  Google Scholar 

  100. Evans RM, You H, Hameed S et al (2010) Heterodimerization of ORL1 and opioid receptors and its consequences for N-type calcium channel regulation. J Biol Chem 285(2):1032–1040

    PubMed  CAS  Google Scholar 

  101. Pan YX, Bolan E, Pasternak GW (2002) Dimerization of morphine and orphanin FQ/nociceptin receptors: generation of a novel opioid receptor subtype. Biochem Biophys Res Commun 297(3):659–663

    PubMed  CAS  Google Scholar 

  102. Aicher SA, Punnoose A, Goldberg A (2000) mu-Opioid receptors often colocalize with the substance P receptor (NK1) in the trigeminal dorsal horn. J Neurosci 20(11):4345–4354

    PubMed  CAS  Google Scholar 

  103. Aicher SA, Sharma S, Cheng PY, Liu-Chen LY, Pickel VM (2000) Dual ultrastructural localization of mu-opiate receptors and substance p in the dorsal horn. Synapse 36(1):12–20

    PubMed  CAS  Google Scholar 

  104. Murtra P, Sheasby AM, Hunt SP, De Felipe C (2000) Rewarding effects of opiates are absent in mice lacking the receptor for substance P. Nature 405(6783):180–183

    PubMed  CAS  Google Scholar 

  105. Ripley TL, Gadd CA, De Felipe C, Hunt SP, Stephens DN (2002) Lack of self-administration and behavioural sensitisation to morphine, but not cocaine, in mice lacking NK1 receptors. Neuropharmacology 43(8):1258–1268

    PubMed  CAS  Google Scholar 

  106. Pfeiffer M, Kirscht S, Stumm R et al (2003) Heterodimerization of substance P and mu-opioid receptors regulates receptor trafficking and resensitization. J Biol Chem 278(51):51630–51637

    PubMed  CAS  Google Scholar 

  107. Pfeiffer M, Koch T, Schroder H, Laugsch M, Hollt V, Schulz S (2002) Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization. J Biol Chem 277(22):19762–19772

    PubMed  CAS  Google Scholar 

  108. Pfeiffer M, Koch T, Schroder H et al (2001) Homo- and heterodimerization of somatostatin receptor subtypes. Inactivation of sst(3) receptor function by heterodimerization with sst(2A). J Biol Chem 276(17):14027–14036

    PubMed  CAS  Google Scholar 

  109. Peterson PK, Molitor TW, Chao CC (1998) The opioid-cytokine connection. J Neuroimmunol 83(1–2):63–69

    PubMed  CAS  Google Scholar 

  110. Chen C, Li J, Bot G, Szabo I, Rogers TJ, Liu-Chen LY (2004) Heterodimerization and cross-desensitization between the mu-opioid receptor and the chemokine CCR5 receptor. Eur J Pharmacol 483(2–3):175–186

    PubMed  CAS  Google Scholar 

  111. Guo XH, Fairbanks CA, Stone LS, Loh HH (2003) DPDPE-UK14, 304 synergy is retained in mu opioid receptor knockout mice. Pain 104(1–2):209–217

    PubMed  CAS  Google Scholar 

  112. Milner TA, Drake CT, Aicher SA (2002) C1 adrenergic neurons are contacted by presynaptic profiles containing DELTA-opioid receptor immunoreactivity. Neuroscience 110(4):691–701

    PubMed  CAS  Google Scholar 

  113. Robertson B, Schulte G, Elde R, Grant G (1999) Effects of sciatic nerve injuries on delta-opioid receptor and substance P immunoreactivities in the superficial dorsal horn of the rat. Eur J Pain 3(2):115–129

    PubMed  CAS  Google Scholar 

  114. Stone LS, Broberger C, Vulchanova L et al (1998) Differential distribution of alpha2A and alpha2C adrenergic receptor immunoreactivity in the rat spinal cord. J Neurosci 18(15):5928–5937

    PubMed  CAS  Google Scholar 

  115. Rios C, Gomes I, Devi LA (2004) Interactions between delta opioid receptors and alpha-adrenoceptors. Clin Exp Pharmacol Physiol 31(11):833–836

    PubMed  CAS  Google Scholar 

  116. Jordan BA, Trapaidze N, Gomes I, Nivarthi R, Devi LA (2001) Oligomerization of opioid receptors with beta 2-adrenergic receptors: a role in trafficking and mitogen-activated protein kinase activation. Proc Natl Acad Sci USA 98(1):343–348

    PubMed  CAS  Google Scholar 

  117. Grimm MC, Ben-Baruch A, Taub DD et al (1998) Opiates transdeactivate chemokine receptors: delta and mu opiate receptor-mediated heterologous desensitization. J Exp Med 188(2):317–325

    PubMed  CAS  Google Scholar 

  118. Parenty G, Appelbe S, Milligan G (2008) CXCR2 chemokine receptor antagonism enhances DOP opioid receptor function via allosteric regulation of the CXCR2-DOP receptor hetero-dimer. Biochem J 412:245–256

    PubMed  CAS  Google Scholar 

  119. Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ (2001) A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106(5):619–632

    PubMed  CAS  Google Scholar 

  120. Lembo PM, Grazzini E, Groblewski T et al (2002) Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs. Nat Neurosci 5(3):201–209

    PubMed  CAS  Google Scholar 

  121. Grazzini E, Puma C, Roy MO et al (2004) Sensory neuron-specific receptor activation elicits central and peripheral nociceptive effects in rats. Proc Natl Acad Sci USA 101(18):7175–7180

    PubMed  CAS  Google Scholar 

  122. Breit A, Gagnidze K, Devi LA, Lagace M, Bouvier M (2006) Simultaneous activation of the delta opioid receptor (deltaOR)/sensory neuron-specific receptor-4 (SNSR-4) hetero-oligomer by the mixed bivalent agonist bovine adrenal medulla peptide 22 activates SNSR-4 but inhibits deltaOR signaling. Mol Pharmacol 70(2):686–696

    PubMed  CAS  Google Scholar 

  123. Szabo I, Wetzel MA, Zhang N et al (2003) Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization. J Leukoc Biol 74(6):1074–1082

    PubMed  CAS  Google Scholar 

  124. Pello OM, Martinez-Munoz L, Parrillas V et al (2008) Ligand stabilization of CXCR4/delta-opioid receptor heterodimers reveals a mechanism for immune response regulation. Eur J Immunol 38(2):537–549

    PubMed  CAS  Google Scholar 

  125. Tai KK, Jin WQ, Chan TK, Wong TM (1991) Characterization of [3H]U69593 binding sites in the rat heart by receptor binding assays. J Mol Cell Cardiol 23(11):1297–1302

    PubMed  CAS  Google Scholar 

  126. Ventura C, Bastagli L, Bernardi P, Caldarera CM, Guarnieri C (1989) Opioid receptors in rat cardiac sarcolemma: effect of phenylephrine and isoproterenol. Biochim Biophys Acta 987(1):69–74

    PubMed  CAS  Google Scholar 

  127. Daniels DJ, Kulkarni A, Xie Z, Bhushan RG, Portoghese PS (2005) A bivalent ligand (KDAN-18) containing delta-antagonist and kappa-agonist pharmacophores bridges delta2 and kapp a1 opioid receptor phenotypes. J Med Chem 48(6):1713–1716

    PubMed  CAS  Google Scholar 

  128. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46(1–3):3–26

    PubMed  CAS  Google Scholar 

  129. Waldhoer M, Fong J, Jones RM et al (2005) A heterodimer-selective agonist shows in vivo relevance of G-protein-coupled receptor dimers. Proc Natl Acad Sci USA 102(25):9050–9055

    PubMed  CAS  Google Scholar 

  130. Matthes HW, Maldonado R, Simonin F et al (1996) Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 383(6603):819–823

    PubMed  CAS  Google Scholar 

  131. Nitsche JF, Schuller AG, King MA, Zengh M, Pasternak GW, Pintar JE (2002) Genetic dissociation of opiate tolerance and physical dependence in delta-opioid receptor-1 and preproenkephalin knock-out mice. J Neurosci 22(24):10906–10913

    PubMed  CAS  Google Scholar 

  132. Guan JS, Xu ZZ, Gao H et al (2005) Interaction with vesicle luminal protachykinin regulates surface expression of delta-opioid receptors and opioid analgesia. Cell 122(4):619–631

    PubMed  CAS  Google Scholar 

  133. Cahill CM, Morinville A, Lee MC, Vincent JP, Collier B, Beaudet A (2001) Prolonged morphine treatment targets delta opioid receptors to neuronal plasma membranes and enhances delta-mediated antinociception. J Neurosci 21(19):7598–7607

    PubMed  CAS  Google Scholar 

  134. Morinville A, Cahill CM, Esdaile MJ et al (2003) Regulation of delta-opioid receptor trafficking via mu-opioid receptor stimulation: evidence from mu-opioid receptor knock-out mice. J Neurosci 23(12):4888–4898

    PubMed  CAS  Google Scholar 

  135. Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG (2000) Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408(6813):720–723

    PubMed  CAS  Google Scholar 

  136. Gupta A, Mulder J, Gomes I, Rozenfeld R, Bushlin I, Ong E, Lim M, Maillet, E, Juneck M, Cahill CM, Harkany T, Devi LA (2010) Increased abundance of opioid receptor heteromers after chronic morphine administration. Sci.Signal. 3:ra54

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, 19-84 Annenberg Building, One Gustave L. Levy Place, New York, NY, 10029, USA

    Lakshmi A. Devi

Authors
  1. Raphael Rozenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ivone Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lakshmi A. Devi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lakshmi A. Devi .

Editor information

Editors and Affiliations

  1. , Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10065, New York, USA

    Gavril W. Pasternak

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Rozenfeld, R., Gomes, I., Devi, L.A. (2011). Opioid Receptor Dimerization. In: Pasternak, G. (eds) The Opiate Receptors. The Receptors. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-993-2_15

Download citation

Publish with us

Policies and ethics

Search

Navigation